Alterations of the Sympathoadrenal Axis Related to the Development of Alzheimer’s Disease in the 3xTg Mouse Model

Alzheimer’s disease (AD), the most common form of dementia, is becoming a global health problem and public health priority. In the advanced stages of AD, besides the initial cognitive symptoms, behavioral problems, particularly agitation and aggressiveness, become prevalent in AD patients. These non-cognitive symptoms could be related to a noradrenergic overactivation. In this study, we used chromaffin cells (CCs) isolated from the adrenal gland of 3xTg AD model mice to characterize potential alterations in the autocrine-paracrine modulation of voltage-dependent calcium channels (VDCCs), which in turn serve to regulate the release of catecholamines. We used mice at the presymptomatic stage (2 months) and mice over 12 months of age, when AD-related cognitive impairment was fully established. We found that the modulation of inward currents through VDCCs induced by extracellular ATP was stronger in CCs isolated from the adrenal medulla of 3xTg mice older than 12 months of age, an effect likely related to disease progression as it was not observed in CCs from age-matched WT mice. This enhanced modulation leads to increased catecholamine release in response to stressful situations, which may explain the non-cognitive behavioral problems found in AD patientsThis research was funded by the Spanish Ministerio de Economía y Competitividad (MINECO), grant number SAF2017-78892-R. Additionally, A.M.M. has a fellowship from the Spanish Ministerio de Ciencia, Innovación y Universidades (Ref. FPU2016/02559

N-benzylpiperidine derivatives as α7 nicotinic receptor antagonists

This document is the accepted manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience 7.8, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see DOI: 10.1021/acschemneuro.6b00122.A series of multitarget directed propargylamines, as well as other differently susbstituted piperidines have been screened as potential modulators of neuronal nicotinic acetylcholine receptors (nAChRs). Most of them showed antagonist actions on α7 nAChRs. Especially, compounds 13, 26, and 38 displayed submicromolar IC50 values on homomeric α7 nAChRs, whereas they were less effective on heteromeric α3β4 and α4β2 nAChRs (up to 20-fold higher IC50 values in the case of 13). Antagonism was concentration dependent and noncompetitive, suggesting that these compounds behave as negative allosteric modulators of nAChRs. Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for α7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca2+ signals mediated by nAChRs. Finally, compounds 38 and 13 inhibited 5-HT3A serotonin receptors whereas they had no effect on α1 glycine receptors. Given the multifactorial nature of many pathologies in which nAChRs are involved, these piperidine antagonists could have a therapeutic potential in cases where cholinergic activity has to be negatively modulated.This work was supported by grants SAF2011-22802 to S.S., SAF2012-33304 to J.M.-C., CSD2008-00005 (the Spanish Ion Channel Initiative-CONSOLIDER INGENIO 2010) to M.C. from the Spanish Ministry of Science and Innovation (Ministerio de Economía y Competitividad)

SoxD genes are required for adult neural stem cell activation

19 páginas, 6 figuras. Supplemental information can be found online at https://doi.org/10.1016/j. celrep.2022.110313.The adult neurogenic niche in the hippocampus is maintained through activation of reversibly quiescent neural stem cells (NSCs) with radial glia-like morphology (RGLs). Here, we show that the expression of SoxD transcription factors Sox5 and Sox6 is enriched in activated RGLs. Using inducible deletion of Sox5 or Sox6 in the adult mouse brain, we show that both genes are required for RGL activation and the generation of new neurons. Conversely, Sox5 overexpression in cultured NSCs interferes with entry in quiescence. Mechanistically, expression of the proneural protein Ascl1 (a key RGL regulator) is severely downregulated in SoxD-deficient RGLs, and Ascl1 transcription relies on conserved Sox motifs. Additionally, loss of Sox5 hinders the RGL activation driven by neurogenic stimuli such as environmental enrichment. Altogether, our data suggest that SoxD genes are key mediators in the transition of adult RGLs from quiescence to an activated mitotic state under physiological situations.This work was funded by grants to A.V.M. from the Spanish MICINN (SAF2017-85717-R, PID2020-112989RB-I00) and F. Alicia Koplowitz (2018) and to H.M. from the Spanish MICINN (SAF2015-70433-R, PID2019- 111225RB-I00) and PROMETEO/2018/055 from Generalitat ValencianaPeer reviewe

Alterations of the Sympathoadrenal Axis Related to the Development of Alzheimer’s Disease in the 3xTg Mouse Model

Alzheimer’s disease (AD), the most common form of dementia, is becoming a global health problem and public health priority. In the advanced stages of AD, besides the initial cognitive symptoms, behavioral problems, particularly agitation and aggressiveness, become prevalent in AD patients. These non-cognitive symptoms could be related to a noradrenergic overactivation. In this study, we used chromaffin cells (CCs) isolated from the adrenal gland of 3xTg AD model mice to characterize potential alterations in the autocrine-paracrine modulation of voltage-dependent calcium channels (VDCCs), which in turn serve to regulate the release of catecholamines. We used mice at the presymptomatic stage (2 months) and mice over 12 months of age, when AD-related cognitive impairment was fully established. We found that the modulation of inward currents through VDCCs induced by extracellular ATP was stronger in CCs isolated from the adrenal medulla of 3xTg mice older than 12 months of age, an effect likely related to disease progression as it was not observed in CCs from age-matched WT mice. This enhanced modulation leads to increased catecholamine release in response to stressful situations, which may explain the non-cognitive behavioral problems found in AD patients

Calcium entry through slow-inactivating L-type calcium channels preferentially triggers endocytosis rather than exocytosis in bovine chromaffin cells

Calcium (Ca2+)-dependent endocytosis has been linked to preferential Ca2+ entry through the L-type (α1D, CaV1.3) of voltage-dependent Ca2+ channels (VDCCs). Considering that the Ca2+-dependent exocytotic release of neurotransmitters is mostly triggered by Ca2+ entry through N-(α1B, CaV2.2) or PQ-VDCCs (α1A, CaV2.1) and that exocytosis and endocytosis are coupled, the supposition that the different channel subtypes are specialized to control different cell functions is attractive. Here we have explored this hypothesis in primary cultures of bovine adrenal chromaffin cells where PQ channels account for 50% of Ca2+ current (ICa), 30% for N channels, and 20% for L channels. We used patch-clamp and fluorescence techniques to measure the exo-endocytotic responses triggered by long depolarizing stimuli, in 1, 2, or 10 mM concentrations of extracellular Ca2+ ([Ca2+]e). Exo-endocytotic responses were little affected by ω-conotoxin GVIA (N channel blocker), whereas ω -agatoxin IVA (PQ channel blocker) caused 80% blockade of exocytosis as well as endocytosis. In contrast, nifedipine (L channel blocker) only caused 20% inhibition of exocytosis but as much as 90% inhibition of endocytosis. Conversely, FPL67146 (an activator of L VDCCs) notably augmented endocytosis. Photoreleased caged Ca2+ caused substantially smaller endocytotic responses compared with those produced by K+ depolarization. Using fluorescence antibodies, no colocalization between L, N, or PQ channels with clathrin was found; a 20-30% colocalization was found between dynamin and all three channel antibodies. This is incompatible with the view that L channels are coupled to the endocytotic machine. Data rather support a mechanism implying the different inactivation rates of L (slow-inactivating) and N/PQ channels (fast-inactivating). Thus a slow but more sustained Ca2+ entry through L channels could be a requirement to trigger endocytosis efficiently, at least in bovine chromaffin cells. © 2011 the American Physiological Society.This work was partially supported from the following grants from Spanish institutions (to A. G. Garcia): SAF2006-03589 and SAF2010-21795, Ministerio de Ciencia e Innovación, Spain; NDE 07/09, Agencia Laín Entralgo, Comunidad de Madrid; PI016/09, Fundación C.I.E.N., Instituto de Salud Carlos III; RD 06/0026 RETICS, Instituto de Salud Carlos III; S-SAL-0275-2006, Comunidad de Madrid. Also by Grant SAF2007-65181 and SAL-2010-18837, Ministerio de Ciencia e Innovación, Spain (to L. Gandia).Peer Reviewe

Generation of quiescence sub-states in neural stem cells during the development of the hippocampal neurogenic niche

Peer reviewe

Analysis of hippocampal participation in social interactions in a genetic model of autism spectrum disorder

FEMS Forum, 9-13 July, Paris.Peer reviewe